EP0754031B1 - Multilamellare anzneistoffabgabesysteme - Google Patents

Multilamellare anzneistoffabgabesysteme Download PDF

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Publication number
EP0754031B1
EP0754031B1 EP95916160A EP95916160A EP0754031B1 EP 0754031 B1 EP0754031 B1 EP 0754031B1 EP 95916160 A EP95916160 A EP 95916160A EP 95916160 A EP95916160 A EP 95916160A EP 0754031 B1 EP0754031 B1 EP 0754031B1
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EP
European Patent Office
Prior art keywords
acid
glyceryl
pharmaceutical preparation
hydrophobic
long chain
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EP95916160A
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English (en)
French (fr)
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EP0754031A4 (de
EP0754031A1 (de
Inventor
George W. Belenduik
Edward M. Rudnic
John A. Mccarty
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Supernus Pharmaceuticals Inc
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Shire Laboratories Inc
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes

Definitions

  • the ability of drugs to be administered via the oral route depends on several factors.
  • the drug must be soluble in the gastrointestinal fluids in order for the drug to be transported across biological membranes, or be suitable for an active transport mechanism.
  • Very small particulates (less than 300 nanometers) can be absorbed through the Peyer's Patch system in the small intestine, and through the lymphatic system, but this mechanism is not capable of absorbing large doses of drugs into the systemic circulation.
  • the primary issue in the ability to deliver peptides orally is the protection of the drug from proteolytic enzymes.
  • the first is an "enteric" coating that can be applied to release the drug only in neutral to basic pH, so that the peptide is not exposed to gastric juices.
  • This approach alone is not sufficient to protect the peptide since proteolytic enzymes exist in the upper intestinal tract, and some degradation of the drug can still occur.
  • the other approach is to incorporate the peptide in a hydrophobic material so that aqueous fluids cannot penetrate the system. In this way, the peptide is protected from proteolytic enzymes.
  • US 4,963,365 discloses a controlled release pharmaceutical dosage form, which consists essentially of a water-soluble core containing diltiazem hydrochloride, an inner coating layer composed of ethylcellulose and a hydrophobic substance selected from the group consisting of talc and an alkali earth metal stearate.
  • GB 2 009 698 discloses micro capsules encapsulated by a film containing at least three alternating layers of hydrophilic and hydrophobic colloid materials.
  • a pharmaceutical preparation or delivery system including a pharmaceutical agent incorporated into particles comprising (i) a core formed from a hydrophilic material, a hydrophobic material or a hydrophobic emulsion or dispersion and (ii) an alternating sequence of hydrophilic/hydrophobic layers thereon such that there is a hydrophilic/hydrophobic interface between the core and each succeeding layer as claimed in claim 1.
  • a pharmaceutical agent incorporated into particles comprising (i) a core formed from a hydrophilic material, a hydrophobic material or a hydrophobic emulsion or dispersion and (ii) an alternating sequence of hydrophilic/hydrophobic layers thereon such that there is a hydrophilic/hydrophobic interface between the core and each succeeding layer as claimed in claim 1.
  • Preferred embodiments are claimed in dependent claims 2-16.
  • the particles include the core or prill seed and multiple alternating hydrophobic and hydrophilic layers, forming solid-state or semi-solid vesicles, in a multilamellar structure.
  • the core can be formed of hydrophilic or hydrophobic materials or of a hydrophobic discontinuous phase emulsified or dispersed in a hydrophilic continuous phase, in which case the surface of the core or seed will take on the hydrophilic character of the continuous phase.
  • the surfactant and the two phases stabilized form an emulsion.
  • This emulsion can take the form of a complex water-in-oil-in-water-etc. emulsion oil-in-water-in-oil-etc. emulsion.
  • Each phase can be very small in size or volume, or can be a discernible coating over the previous phase with a surfactant stabilizing the interface.
  • Hydrophilic and hydrophobic layers are formed onto the core or seed such that there is always an alternating hydrophilic/hydrophobic interface formed. Thus, a core with a hydrophilic surface will first be coated with a hydrophobic layer followed by a hydrophilic layer, and vice versa.
  • Drugs of the type delivered by the delivery system of the invention partition into either or both phases, according to the drugs' partition coefficient and are released from the particles by diffusion and erosion of the vesicle in vivo.
  • the spheres can be delivered by the oral, nasal, otic or inhalation routes of administration and have a size range of from 0.5 to about 100 ⁇ m (microns).
  • the hydrophobic material forms the discontinuous phase and the hydrophilic material forms the continuous phase in which the hydrophobic material is emulsified.
  • the hydrophobic discontinuous phase and the hydrophilic continuous phase can each independently be solid, semisolid or liquid.
  • the pharmaceutical agent may be dispersed or incorporated into the hydrophobic material, the hydrophilic material or in both the hydrophobic and hydrophilic materials.
  • the carrier emulsion is a colloid, microcolloidal emulsion or, most preferably, a microemulsion.
  • An emulsion is a disperse system containing at least two immiscible phases, a hydrophobic phase and a hydrophilic phase.
  • the emulsion comprises the dispersed phase, the dispersion phase and an emulsifying agent or surfactant agent, except when the hydrophobic material is a "self-emulsifying" ester, making a separate emulsifying agent unnecessary.
  • the term “colloidal” refers to emulsions in which the dispersed phase is of very fine particles, usually less than about 1 mm in size.
  • a "microcolloid” is an emulsion wherein the dispersed particles are usually about 100 um or less in size. Cosurfactants are also common components of microcolloids and are simply surfactants included in addition to the primary surfactant.
  • a "microemulsion” is an optically isotropic and thermodynamically stable liquid emulsions.
  • the emulsions of the invention are generally made by adding hot (70-80° C) hydrophobic phase (smaller by weight) to hot (70-80° C) hydrophilic phase (larger by weight) forcing inversion of the surface active agent to form a disperse emulsion of unaggregated dispersed phase particles.
  • the drug is usually added with the hydrophobic material when it is an organic molecule that is poorly soluble in aqueous media.
  • the drug is usually added after the emulsion has been formed and allowed to cool when it is a peptide.
  • the drug in emulsion formulation is then filled into a soft or hard gelatin capsule, tablet or other oral dosage form.
  • certain hydrophobic materials provide enhanced absorption capabilities for oral delivery of peptide drugs and drugs that are poorly soluble in aqueous media.
  • these materials are selected from the group consisting of long chain carboxylic acids, long chain carboxylic acid esters, long chain carboxylic acid alcohols and mixtures thereof.
  • Certain long chain carboxylic acid esters are self-emulsifying, that is that a surfactant is not necessary for these compounds to be emulsified into a hydrophilic phase.
  • the long chain carboxylic acids generally contain from 6-30 carbon atoms and preferably contains at least 12 carbon atoms, most preferably 12 to 22. In some cases this carbon chain is fully saturated and unbranched, while others contain one or more double bonds. A few contain 3-carbon rings or hydroxyl groups.
  • the saturated straight chain acids are selected from the group consisting of n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid and melissic acid.
  • unsaturated monoolefinic straight chain monocarboxylic acids which are selected from the group consisting of oleic acid, gadoleic acid and erucic acid.
  • unsaturated (polyolefinic) straight chain monocaboxyic acids which are selected from the group consisting of linoleic acid, linolenic acid, arachidonic acid and behenolic acid.
  • Useful branched acids are diacetyl tartaric acid.
  • the long chain carboxylic acid esters are selected from the group consisting of: glyceryl monostearates; glyceryl monopalmitates; mixtures of glyceryl monostearate and glyceryl monopalmitate (Myvaplex 600, Eastman Fine Chemical Company); glyceryl monolinoleate; glyceryl monooleate; mixtures of glyceryl monopalmitate, glyceryl monostearate glyceryl monooleate and glyceryl monolinoleate (Myverol 18-92, Eastman Fine Chemical Company); glyceryl monolinolenate; glyceryl monogadoleate; mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolinolenate and glyceryl monogadoleate (Myverol 18-99, Eastman Fine Chemical
  • Examples of the self-emulsifying long chain carboxylic acid esters include those from the groups of stearates, palmitates, ricinoleates, oleates, behenates, ricinolenates, myristates, laurates, caprylates, and caproates.
  • the alcohols useful in the invention are exemplified by the hydroxyl forms of the carboxylic acids exemplified above and also cetearyl alcohol.
  • the types of protective or sustained release coatings that can be used include, but are not limited to, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and esters of methacrylic and ethacrylic acid (Eudragit RL, RS, and NE polymer products, Rohm Pharma, Darmstadt, Germany).
  • the enteric protective materials or coatings can be, for example, cellulose acetate pthalate, hydroxypropylmethylcellulose pthalate, ethylvinylacetate pthalate, polyvinylacetate pthalate and esters of methacrylic and ethacrylic acid (Eudragit S and Eudragit L, Rohm Pharma, Darmstadt, Ger.).
  • composition or preparation of the invention can further include a surfactant, an amphiphilic molecule consisting of a hydrophobic tail and a hydrophilic head. These molecules possess distinct regions of both hydrophilic and hydrophobic character.
  • the hydrophobic tai can be a hydrocarbon or fluorocarbon chain of 8 to 18 carbon atoms.
  • the hydrophilic head can be ammonium, sulfate, sulfonate or carboxylate if ionic, and polyoxyethylene if non-ionic. They are long chain molecules such as, for example, soaps or detergents.
  • Surfactants accumulate at the hydrophilic/hydrophobic (water/oil) interface and lower the surface tension.
  • Surface active agents or surfactant are long chain molecules, such as soaps and detergents, which accumulate at the hydrophilic/hydrophobic(water/oil) interface and lower the surface tension.
  • One effect of a reduced surface tension is the stabilization of the emulsions. This is because molecules with both polar and non-polar groups become oriented such that the hydrocarbon tail embeds itself into the hydrophobic phase and the hydrophilic head protrudes into the hydrophilic phase.
  • a surface-active agent such as a surfactant
  • it is usually present in amounts of about 0.05% to 10.0% weight/weight of the hydrophobic composition with a preferred range of 0.1% to 2.0% (w/w).
  • the drugs to be incorporated individually or as combinations in the pharmaceutical preparations of the invention are those having less than about 80% oral bioavailability.
  • bioavailability means the rate and extent of systemic absorption of a drug from the oral route of administration.
  • the drug is a polypeptide, usually of less than 15 amino acids.
  • examples include cyclosporin, angiotensin I, II and III, enkephalins and their analogs, ACTH, antiinflammatory peptides I, II, III, bradykinin, calcitonin, cholecystikinin (CCK) fragments 26-33 and 30-33; pre/pro CCK (V-9-M), ⁇ -endorphin, dinorphin, leucokinin, leutinizing hormone releasing hormone (LHRH), neurokinins (e.g. neurokinin A), somatostatin, substance P, thyroid releasing hormone (TRH) and vasopressin.
  • pre/pro CCK V-9-M
  • ⁇ -endorphin ⁇ -endorphin, dinorphin, leucokinin, leutinizing hormone releasing hormone (LHRH)
  • neurokinins e.g. neurokinin A
  • TRH thyroid releasing hormone
  • the drug is an organic molecule that is poorly soluble in aqueous media.
  • organic molecules usually have a molecular weight (m.w.) of less than 1,000 daltons, and usually less than 600 daltons.
  • examples include acyclovir, adriamycin, cabamazepine, griseofulvin, angiotensin converting enzyme inhibitors, flutamide, melphalan, nifedipine, indomethacin, naproxen, estrogens, testosterones, steroids, phenytoin, sumatripan, ergotamines and cannabinoids.
  • drugs are incorporated into hydrophobic materials by admixture using conventional mixing devices and homogenizers used for semi-solid ointments and lotions, with agitation at speeds common to emulsified products such as creams and emulsions.
  • common equipment are propeller or turbine mixers, homogenizers, colloid mills, ultrasonic mixers and microfluidizers.
  • the shear of the agitation should be sufficient to form a stable dispersion, but not too great to cause degradation of the drug.
  • Suitable homogenizers are available from Micromedics, Inc., Silverson, APV Crepaco and Arde Barinco.
  • This hydrophobic emulsion or dispersion is then formed into particles by spray-congealing or "prilling.”
  • This process uses a spray nozzle which atomizes the material in a cooling tower. As the material is sprayed, surface tension causes a uniform spherical particle to be formed. As the particle falls through the cooling chamber, it hardens into a stable, intact sphere.
  • These spheres can be sprayed in a variety of diameters, generally from 0.5 ⁇ m (microns) to 100 ⁇ m (microns). It is preferred to reduce the size of the sphere as much as possible, preferably below 5 ⁇ m (microns) for the primary hydrophobic "seed" prill.
  • a fluidized bed apparatus with an alternating sequence of (i) a surfactant-containing hydrophilic solution and (ii) a stable emulsion or dispersion of the drug in a hydrophobic material to provide the multilamellar drug delivery system of the invention.
  • the hydrophilic phase is sprayed on with a binder that adheres to the hydrophobic seed.
  • a hydrophobic material is sprayed on which will adhere the aqueous surfactant phase.
  • What follows is a process of repeatedly alternating between these two steps in a fluid bed apparatus. This is done in one fluid bed that has differential pressures that organize the flow in that bed.
  • the seed is repeatedly coated with the hydrophilic solution for a set number of minutes and then with the hydrophobic emulsion or dispersion for an independent set number of minutes.
  • the apparatus used is a fluid-bed coating apparatus, such as is available from Wurster and others.
  • the newly coated particles are then coated with the hydrophobic mixture from above, and then alternating hydrophilic and hydrophobic coatings to produce a multilamellar structure.
  • the drug partitions into each phase, according to its partition coefficient, and is released from the system by diffusion, erosion, and enhanced dissolution resulting from the surface-active nature of the interfaces.
  • the particles can be incorporated into hard gelatin capsules, either with additional excipients, or alone.
  • Typical excipients to be added to a capsule formulation include, but are not limited to: fillers such as microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler.
  • fillers such as microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler.
  • there can be flow aids such as fumed silicon dioxide, silica gel, magnesium stearate, calcium stearate or any other material imparting flow to powders. Because of their hydrophobic nature, the particles should not need a lubricant, but one can be added if necessary by using polyethylene glycol, leucine, glyceryl behenate, magnesium stearate or
  • the particles may also be incorporated into a tablet, in particular by incorporation into a tablet matrix, which rapidly disperses the particles after ingestion.
  • a filler/binder In order to incorporate these particles into such a tablet, a filler/binder must be added to a tablet that can accept the particles, but will not allow their destruction during the tableting process.
  • Materials that are suitable for this purpose include, but are not limited to, microcrystalline cellulose (Avicel), soy polysaccharide (Emcosoy), pre-gelatinized starches (STARCH 1500, National 1551), and polyethylene glycols (Carbowax). The materials should be present in the range of 5-75% (w/w), with a preferred range of 25-50% (w/w).
  • disintegrants are added in order to disperse the particles once the tablet is ingested.
  • Suitable disintegrants include, but are not limited to: cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol), sodium starch glycolate (Explotab, Primojel), and cross-linked polyvinylpolypyrrolidone (Plasdone-XL). These materials should be present in the range of 3-15% (w/w), with a preferred range of 5-10% (w/w).
  • Lubricants are also added to assure proper tableting, and these can include, but are not limited to: magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, leucine, glyceryl behanate, and hydrogenated vegetable oil. These lubricants should be present in amounts from 0.1-10% (w/w), with a preferred range of 0.3-3.0% (w/w).
  • Tablets are formed, for example, as follows.
  • the particles are introduced into a blender along with Avicel, disintegrants and lubricant, mixed for a set number of minutes to provide a homogeneous blend which is then put in the hopper of a tablet press with which tablets are compressed.
  • the compression force used is adequate to form a tablet; however, not sufficient to fracture the beads or coatings.
  • the capsule or tablet can also be enteric coated. Either the particles can be enteric coated (Ph sensitive) and released in the stomach or the capsule or tablet can be enteric coated (thereby releasing the particles in the intestine), in which case the particles need not be so coated. To use only a sustained release coating on the particle one would also need an enteric coated capsule or tablet. There are three approaches here. First, there is the uncoated hydrophobic particle in an enteric coated capsule. Second, there is the sustained release coated particle within an enteric coated capsule or tablet. Third, there is the enteric coated particle enclosed within a regular soft gelatin capsule or uncoated tablet.
  • the capsule may be further processed to provide gastric protection by enterically coating the capsule.
  • enterically coating the capsule When the contents of the capsule are released into the gastrointestinal milieu, it spontaneously forms a microcolliodal emulsion with the gastrointestinal fluid.
  • the gastrointestinal fluid acting as the aqueous phase.
  • an emulsion based system requires that the drug be dispered into the hydrophobic material as described above, with the aqueous phase being added in the presence of surfactant or self-emulsifying hydrophobic long chain carboxylic acid ester. This procedure under suitable shear forms a microemulsion. This emulsion is then filled into a soft of hard gelatin capsule. The capsule may be further processed to provide gastric protection by enterically coating the capsule.

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Claims (16)

  1. Pharmazeutisches Präparat, enthaltend ein pharmazeutisches Mittel, das Teilchen einverleibt ist, die folgendes umfassen: (i) einen aus einem hydrophilen Material, einem hydrophoben Material oder einer hydrophoben Emulsion oder Dispersion gebildeten Kern und (ii) darauf eine abwechselnde Folge von hydrophilen/hydrophoben Schichten, die so beschaffen sind, dass eine hydrophile/hydrophobe Grenzfläche zwischen dem Kern und jeder folgenden Schicht vorhanden ist, wobei das pharmazeutische Präparat ein hydrophobes Material umfasst, das aus der Gruppe langkettige Carbonsäuren, langkettige Carbonsäureester, langkettige Carboxylalkohole und Gemische davon ausgewählt ist, wobei die langkettige Carbonsäure aus der Gruppe n-Dodecansäure, n-Tetradecansäure, n-Hexadecansäure, Capronsäure, Caprylsäure, Caprinsäure, Laurinsäure, Myristinsäure, Palmitinsäure, Stearinsäure, Arachidinsäure, Behinsäure, Montansäure, Melissinsäure, Ölsäure, Gadoleinsäure, Erucasäure, Linolsäure, Linolensäure, Arachidonsäure, Behenolsäure und Diacetylweinsäure ausgewählt ist, wobei der langkettige Carbonsäureester aus der Gruppe Glycerylmonostearate; Glycerylmonopalmitate; Gemische von Glycerylmonostearat und Glycerylmonopalmitat; Glycerylmonolinoleat; Glycerylmonooleat; Gemische von Glycerylmonopalmitat, Glycerlymonostearat, Glycerylmonooleat und Glycerylmonolinoleat; Glycerlymonolinolenat; Glycerylmonogadoleat; Gemische von Glycerylmonopalmitat, Glycerylmonostearat, Glycerylmonooleat, Glycerylmonolinoleat, Glycerylmonolinolenat und Glycerylmonogadoleat; acetylierte Glyceride, wie destillierte, acetylierte Monoglyceride; Gemische von Propylenglycolmonoestern, destillierten Monoglyceriden, Natriumstearoyllactylat und Siliciumdioxid; Gemische von Propylenglycolmonoestern, destillierten Monoglyceriden, Natriumstearoyllactylat und Siliciumdioxid; d-alpha-Tocopherolpolyethylenglycol-1000-succinat; Gemische von Mono- und Diglyceridestern; Calciumstearoyllactylat; ethoxylierte Mono- und Diglyceride; lactierte Mono- und Diglyceride; Lactylatcarbonsäureester von Glycerin und Propylenglycol; Lactylester von langkettigen Carbonsäuren; Polyglycerinester von langkettigen Carbonsäuren, Propylenglycolmono- und -diester von langkettigen Carbonsäuren; Natriumstearoyllactylat; Sorbitanmonostearat; Sorbitanmonooleat; weitere Sorbitanester von langkettigen Carbonsäuren; succinylierte Monoglyceride; Stearylmonoglycerylcitrat; Stearylheptanoat; Cetylester von Wachsen; Cetearyloctanoat; C10-C30-Cholesterin/Lavosterolester; und Ester von Saccharose mit langkettigen Carbonsäuren ausgewählt ist und wobei der langkettige Carbonsäurealkohol aus der Gruppe n-Dodecansäurealkohol, n-Tetradecansäurealkohol, n-Hexadecansäurealkohol, Capronsäurealkohol, Caprylsäurealkohol, Caprinsäurealkohol, Laurinsäurealkohol, Myristinsäurealkohol, Palmitinsäurealkohol, Stearinsäurealkohol, Arachidinsäurealkohol, Behensäurealkohol, Montansäurealkohol, Melissinsäurealkohol, Ölsäurealkohol, Gadoleinsäurealkohol, Erucasäurealkohol, Behenolsäurealkohol und Diacetylweinsäurealkohol ausgewählt ist.
  2. Pharmazeutisches Präparat nach Anspruch 1, wobei die Teilchen einen Durchmesser von 0,5 bis 100 µm (Micron) aufweisen.
  3. Pharmazeutisches Präparat nach Anspruch 2, wobei die Teilchen einen Durchmesser von weniger als 10 µm (Micron) aufweisen.
  4. Pharmazeutisches Präparat nach Anspruch 1, wobei die Emulsion oder Dispersion aus folgender Gruppe ausgewählt sind: eine kolloidale Emulsion, eine mikrokolloidale Emulsion und eine Mikroemulsion.
  5. Pharmazeutisches Präparat nach Anspruch 1, wobei die hydrophobe Emulsion ein selbstemulgierendes, oberflächenaktives, hydrophobes Material umfasst.
  6. Pharmazeutisches Präparat nach Anspruch 5, wobei das selbstemulgierende, hydrophobe Material aus folgender Gruppe ausgewählt ist: Stearate, Palmitate, Rhizinoleate, Oleate, Behenate, Rhizinolenate, Myristate, Laurate, Caprylate und Caproate.
  7. Pharmazeutisches Präparat nach Anspruch 1, wobei ein oberflächenaktives Mittel in einem Bereich von 0,05 bis 2,0 % (Gew./Gew.) der hydrophoben Zusammensetzung vorhanden ist.
  8. Pharmazeutisches Präparat nach Anspruch 7, wobei das oberflächenaktive Mittel aus folgender Gruppe ausgewählt ist: Poloxamere, Natriumlaurylsulfat, Sorbitanfettsäureester und Saccharoseester von Fettsäuren.
  9. Pharmazeutisches Präparat nach Anspruch 1, wobei das pharmazeutische Mittel eine biologische Verfügbarkeit von weniger als 80 % aufweist.
  10. Pharmazeutisches Präparat nach Anspruch 1, wobei das pharmazeutische Mittel ein Polypeptid mit bis zu 15 Aminosäuren ist.
  11. Pharmazeutisches Präparat nach Anspruch 10, wobei das Polypeptid bis zu 12 Aminosäuren aufweist.
  12. Pharmazeutisches Präparat nach Anspruch 1, wobei das pharmazeutische Mittel ein organisches Molekül mit weniger als 1000 Dalton ist.
  13. Pharmazeutisches Präparat nach Anspruch 12, wobei das organische Molekül weniger als 600 Dalton aufweist.
  14. Pharmazeutisches Präparat nach Anspruch 1, wobei das pharmazeutische Mittel aus folgender Gruppe ausgewählt ist: Cyclosporin, Angiotensin I, II und III, Enkephaline und deren Analoge, ACTH, entzündungshemmende Peptide I, II, III, Bradykinin, Calcitonin, Cholecystokininfragmente 26-33 und 30-33, Prä/Pro-Cholecystokinin (V-9-M), β-Endorphin, Dinophin, Leukokinin, luteinisierendes Hormon freisetzendes Hormon, Neurokinine, Somatostatin, Substanz P, Thyroidfreisetzendes Hormon, Vasopressin, Acyclovir, Adriamycin, Cabamazepin, Griseofulvin, Angiotensin-converting-Enzym-Inhibitoren, Flutamid, Melphalan, Nifedipin, Indomethacin, Naproxen, Östrogene, Testosterone, Steroide, Phenytoin, Sumatriptan, Ergotamine und Cannabinoide.
  15. Pharmazeutisches Präparat nach Anspruch 1, wobei die Emulsion in einer Kapsel verkapselt ist, die ein erst im Darm lösliches Überzugsmaterial umfasst.
  16. Pharmazeutisches Präparat nach Anspruch 1, wobei die mikrokolloidale Emulsion in einer Kapsel verkapselt ist, die in einer sauren wäßrigen Umgebung löslich ist.
EP95916160A 1994-04-07 1995-04-07 Multilamellare anzneistoffabgabesysteme Expired - Lifetime EP0754031B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US224340 1994-04-07
US08/224,340 US5447729A (en) 1994-04-07 1994-04-07 Multilamellar drug delivery systems
PCT/US1995/004036 WO1995027479A1 (en) 1994-04-07 1995-04-07 Multilamellar drug delivery systems

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EP0754031A1 EP0754031A1 (de) 1997-01-22
EP0754031A4 EP0754031A4 (de) 2000-01-19
EP0754031B1 true EP0754031B1 (de) 2004-03-24

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US (1) US5447729A (de)
EP (1) EP0754031B1 (de)
JP (1) JPH09511744A (de)
AT (1) ATE262317T1 (de)
AU (1) AU695053B2 (de)
CA (1) CA2187202C (de)
DE (1) DE69532753T2 (de)
ES (1) ES2217278T3 (de)
MX (1) MX9604490A (de)
WO (1) WO1995027479A1 (de)

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MX9604490A (es) 1997-11-29
ES2217278T3 (es) 2004-11-01
EP0754031A4 (de) 2000-01-19
CA2187202A1 (en) 1995-10-19
AU2276095A (en) 1995-10-30
DE69532753T2 (de) 2005-01-27
WO1995027479A1 (en) 1995-10-19
EP0754031A1 (de) 1997-01-22
DE69532753D1 (de) 2004-04-29
ATE262317T1 (de) 2004-04-15
JPH09511744A (ja) 1997-11-25
AU695053B2 (en) 1998-08-06
US5447729A (en) 1995-09-05
CA2187202C (en) 2000-11-21

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